Hepatitis B Annual
Home

Current Issue  

Back Issues   

Instructions   

Search Login    Users online: 413 Print this page  Email this page Small font sizeDefault font sizeIncrease font size 
>>> Ahead of Print <<<


 
REVIEW ARTICLE Table of Contents   
Year : 2008  |  Volume : 5  |  Issue : 1  |  Page : 81-94
Chronic delta hepatitis: An overview


Department of Gastroenterology, University of Ankara Medical School, Cebeci Tip Fakultesi Hastanesi, Dikimevi, 06100 Ankara, Turkey

Click here for correspondence address and email

Date of Web Publication9-Jan-2010
 

   Abstract 

Delta hepatitis or hepatitis D leads to acute and chronic liver disease in humans. The causative agent, the hepatitis delta virus (HDV), is a defective virus which leads to hepatitis in humans in the presence of the hepatitis B virus. This helper function of HBV is required for transmission and propagation of HDV infection but not for replication. HDV RNA replication occurs through the double-rolling circle model and does not possess a reverse transcription step. Hepatitis D-induced liver disease is immune-mediated and occurs either as co-infection of both viruses or as superinfection of a hepatitis B carrier with hepatitis D. Based on a sequence variation of 19-38%, to date seven genotypes of HDV have been described. HDV infection has declined significantly in many endemic areas in the last decades, however, due to migration to industrialized countries, this decline appears to have reached a plateau in western countries. The clinical course of delta hepatitis in general is associated with rapid progression. Delta hepatitis may be an additional risk factor for the development of hepatocellular carcinoma. The only established management for delta hepatitis consists of treatment with interferon for a period of at least one year. For those unresponsive to interferon treatment and patients with advanced disease new therapies are an urgent need. Such therapies may be on the horizon but translation of bench work to clinical practice is required.

Keywords: Delta hepatitis, epidemiology, hepatitis D virus, natural history, treatment, virology.

How to cite this article:
Yurdaydin C. Chronic delta hepatitis: An overview. Hep B Annual 2008;5:81-94

How to cite this URL:
Yurdaydin C. Chronic delta hepatitis: An overview. Hep B Annual [serial online] 2008 [cited 2019 Jul 18];5:81-94. Available from: http://www.hepatitisbannual.org/text.asp?2008/5/1/81/58807


Delta hepatitis leads to acute and chronic liver disease in humans. The causative agent, the hepatitis delta virus (HDV), discovered by Rizetto et al., [1] is a defective virus which leads to hepatitis in humans in the presence of the hepatitis B virus (HBV). The association of both viruses in the human condition either occurs as co-infection of hepatitis B and D viruses or as superinfection with HDV of patients who are carriers of the hepatitis B virus. [2] Co-infection causes acute hepatitis. Superinfection with HDV leads to chronic hepatitis in the vast majority of cases. [2],[3] Chronic delta hepatitis represents the most severe form of chronic viral hepatitis and is associated with the most rapid progression of disease among hepatotrop virus infections.

The hepatitis delta virus

The hepatitis delta virus is an approximately 36 nm large particle containing HDV RNA and delta antigen. [2]-[4] HDV RNA is single stranded, highly base-paired, circular and is the smallest genome of any animal virus containing close to 1700 nucleotides. It is coated with envelope protein derived from the pre-S and S antigens of the hepatitis B virus. The production of HBsAg is the only HBV function on which the HDV depends. This helper function of HBV is required for transmission and propagation of HDV infection but not for replication. The HDV RNA has six open reading frames (ORFs) of which only one appears to be actively transcribed. [2],[4] This ORF codes for the hepatitis delta antigen (HDAg). Two HDAgs exist: the small HDAg (24 kd) is 195 amino acids long and the large HDAg (27kd) is 214 amino acids long. The large delta antigen is identical in sequence to the small delta antigen except that it contains an extra 19 amino acids at its carboxyl terminus which is a result of a specific RNA editing event occurring during replication of the HDV genome. The small HDAg is required for HDV RNA replication whereas the large HDAg inhibits HDV RNA synthesis but is necessary for virion morphogenesis. [2],[3],[4]

Replication of HDV RNA occurs through a 'double rolling circle model' in which the genomic strand is replicated by a host RNA polymerase to yield a multimeric linear structure which is then autocatalytically cleaved to linear monomers and ligated into the circular HDV RNA viral progeny [Figure 1].

Based on a sequence variation of 19-38%, to date seven genotypes of HDV have been described [Figure 2]. [5] Since genotypes IIa and IIb in the old nomenclature have only 77% of nucleotide homology, they were assigned to genotypes II and IV in the new nomenclature. Genotypes V, VI and VII have been recently described and these genotypes are based on newly found isolates from Africa. [5] Genotype I is the most prevalent one and distributed throughout the world. [6] It is most common in Mediterranean countries, Africa, Europe and North America. Genotypes II and IV are mostly reported from the Far East and some parts of Russia and are in general associated with a milder disease compared to genotype I. [7],[8] However, a genotype IV (former genotype IIb) variant may be associated with severe liver disease. [9] Genotype III causes the most severe disease and is particularly responsible for outbreaks of fulminant and severe hepatitis in northern South American countries, such as Columbia, Venezuela, Peru and Ecuador. [10]

Epidemiology

HDV is distributed worldwide. The distribution of the disease varies widely and does not exactly reflect the prevalence of HBV infection worldwide. [11] For example, although HBV infection is common in the Far East, HDV infection in the same region is infrequent. Up to 5% of the world's population is known to be infected with HBV and it is considered that at least 5% of all hepatitis B carriers are infected with HDV. With increased control of HBV infection achieved by universal HBV vaccination programs, use of disposable needles, screening blood donors for HBsAg and socioeconomic improvements, HDV infection has declined significantly in many endemic areas like some parts of Southern Europe [12],[13],[14] and Southeast Asia. [15] However, migration from East Europe to West Europe [16] or from poorer countries in general appears to have brought the decline in prevalence to a plateau. [17],[18] On the other hand, in other parts of the Mediterranean basin, such as Turkey, the disease is still endemic [19] and continues to be an important health problem. [20]

Pathogenesis

The pathogenesis of HDV infection remains poorly understood and under-investigated. Liver disease in delta hepatitis is most likely immune mediated. Observation of mononuclear cell infiltration in liver tissue specimens of patients with delta hepatitis and the lack of liver disease in mice made transgenic for both small and large HDAg [21] support this view. One study analyzed proliferative responses of CD4+ T cells to HDV antigen. [22] Overall, 27% of the patients responded to HDV antigen and this response was targeted against different parts of the HDV genome. Only patients with inactive HDV-disease displayed HDV-specific proliferation of CD4+ T cells suggesting that cellular immune responses are able to control HDV. [22] Recently, the contribution of perforin-positive (cytotoxic) CD4 + T cells to the more aggressive course of delta hepatitis has been suggested. [23]

Disease characteristics

Hepatitis D infection develops either as co-infection with hepatitis B or as superinfection of HBsAg carriers with delta viruses. In co-infection, most cases resemble a typical self-limited hepatitis that is clinically and histologically indistinguishable from hepatitis B or other types of viral hepatitis. [3] However, acute HDV infection tends to aggravate the course of the acute HBV infection and is more likely to lead to fulminant hepatitis. [3],[4] But most often it resolves with complete recovery, as typically observed in acute hepatitis B. The rate of chronicity following co-infection is very low (<5%) and similar to that of HBV infection alone.

Superinfection of chronically HBV-infected patients with HDV leads to chronic delta hepatitis in 90% of patients. Only rarely does HDV superinfection result in the clearance of both HDV and HBV. Although there are chronic delta hepatitis cases with a benign course and inactive disease, chronic delta hepatitis, in general, leads to more serious disease compared to chronic hepatitis B and chronic hepatitis C, with an accelerated course and early decompensation. [3] Severe forms are more often seen in patients with a history of intravenous drug use. Furthermore, chronic delta hepatitis may be an additional risk factor for the development of hepatocellular carcinoma (HCC). [24] However, it is also noteworthy that control of HDV in developed countries has resulted not only in dramatic reduction of new HDV cases but also in significant changes in the clinical features of the patients; fresh and severe forms of the disease are less commonly seen, and a majority of the patients have long-standing infections either due to indolent, non-progressive, mild disease or advanced cirrhosis. [25]

In liver transplant recipients, patients with cirrhosis due to HDV have a better prognosis than patients transplanted for HBV-induced cirrhosis. [26] In those patients where HDV infection recurs after transplantation this appears to follow the typical HDV infection pattern through the helper function of HBV. [27]

Treatment

Therapy for chronic delta hepatitis with proven efficacy consists of interferon (IFN) and peginterferon (peg-IFN). In the early 1990s, controlled clinical trials showed that IFN-alpha is effective in chronic hepatitis D but relapse is high and its efficacy is related to the dose and the duration of the therapy. [28],[29],[30] High doses (9-10 million units (MU) thrice weekly or 5 MU daily) for at least one year are required for achieving a better outcome, determined by a biochemical and virologic response (ALT normalization and loss of HDV viremia measured by PCR) both of which correlate with improvement in liver histology. [28],[30] Long-term follow-up (median 13.0 years) of patients in the original study by Farci et al. [28] indicates that high dose interferon may favorably affect the natural history of the disease. [31]

Some patients may need treatment beyond one year. Common sense would suggest that patients with a partial biochemical and virologic response and those who relapse after treatment discontinuation would be the typical candidates for prolonged treatment. Successful eradication of both HBV and HDV in a patient treated daily with interferon for 12 years supports this view. [32] Pilot studies of the use of INF-alpha for 2 years do not appear to show superiority over one year of therapy. [33],[34],[35] However, all of these studies were small cohort studies and did not have a comparator arm of standard one-year treatment. Side effects decreasing compliance to treatment appears to be a problem in prolonged courses of treatment.

Experience with PEG-IFN-alpha has been reported recently by 4 groups. [36],[37],[38],[39] A sustained virologic response, defined as negative HDV RNA 6 months after treatment cessation was reported in 17 to 47% of patients. Differences in dropout rates, in the sensitivities of HDV RNA PCR assays used, in the proportion of patients who had used interferon in the past and who were cirrhotic at baseline may account for the divergent results. Several studies emphasize the importance of measuring HDV RNA at month 6 of treatment, [36],[38],[40] which may predict those who will respond to 1 year of treatment and those who may need extended duration of treatment [Figure 3]. In an analysis of baseline factors predicting response to treatment, patients who were treatment naοve at baseline or who had a low baseline GGT tended to respond better compared to patients who had used IFN in the past or whose baseline GGT was high. [40] In concert with these data, disease of short duration had been previously reported to be predictive of response to treatment. [33] Combination of nucleos(t)ide analogs with interferons with the expectation of better treatment outcomes has failed to show superiority to interferon monotherapy. [35],[36],[39],[40]

Although the HDV has an obligatory dependence on HBV to cause disease, drugs that specifically inhibit HBV replication have shown no effect in CDH. Famciclovir, lamivudine and adefovir have so far been assessed in this context for the treatment of CDH. [39],[40],[41],[42],[43] The most likely reason for this is that none of the current HBV therapies can inhibit the production of HBsAg, the only part of HBV that HDV depends on.

A new nucleoside analog may have therapeutic potential. Clevudine, in the woodchuck hepatitis model, significantly inhibited the production of the surface antigen in a dose-dependent manner. [44] Indeed, in a preliminary study, clevudine was able to significantly decrease HDV RNA in woodchucks infected with HDV. [45]

Another new approach would be the use of prenylation inhibitors. The large, but not the small, delta antigen contains at its carboxyl terminal a cystein containing four amino acid motif? serving as substrate for prenyl transferases which add a prenyl group to the large delta antigen. [46] It has been shown that prenylation of the large delta antigen is necessary for virion morphogenesis. Prenylation inhibitors have been shown to specifically abolish HDV-like particle production in vitro. [47],[48] Recently, antiviral efficacy of prenylation inhibitors has also been reported in the in vivo setting in a mouse-based model of HDV infection [49] which suggests its use in human delta infection. Some prenylation inhibitors have been tested in humans as potential treatment for some malignant tumors and they appear to be without major side effects in humans. [50]

In conclusion, successful treatment of delta hepatitis continues to be confined to the rational use of interferons. However, there are many patients who do not respond to interferons or cannot use them. Development of new treatment strategies is therefore an urgent need.

 
   References Top

1.Rizzetto M, Canese MG, Arico S, Crivelli O, Trepo C, Bonino F, et al. Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers. Gut 1977;18:997-1003.  Back to cited text no. 1      
2.Smedile A, Rizetto M, Gerin JL. Advances in hepatitis D virus biology and disease. Prog Liver Dis 1994;12:157-75.  Back to cited text no. 2      
3.Koytak ES, Yurdaydin C, Glenn JS. Hepatitis D. Curr Treat Options Gastroenterol 2007;10:456-63.  Back to cited text no. 3      
4.Farci P. Delta hepatitis: An update. J Hepatol 2003;39:S212-9.  Back to cited text no. 4      
5.Radjef N, Gordien E, Ivaniushina V, Gault E, Anais P, Drugan T, et al. Molecular phylogenetic analyses indicate a wide and ancient radiation of African hepatitis delta virus, suggesting a delta virus genus of at least seven major clades. J Virol 2004;78:2537-44.  Back to cited text no. 5      
6.Shakil AO, Hadziyannis S, Hoofnagle JH, Di Bisceglie AM, Gerin JL, Casey JL. Geographic distribution and genetic variability of hepatitis delta virus genotype I. Virology 1997;234:160-7  Back to cited text no. 6      
7.Wu JC, Choo KB, Chen CM, Chen TZ, Huo TI, Lee SD. Genotyping of hepatitis D with restriction-fragment length polymorphism and relation to outcome of hepatitis D. Lancet 1995;346:939-41.  Back to cited text no. 7      
8.Sakugawa H, Nakasone H, Nakayoshi T, Kawakami Y, Miyazato S, Kinjo F, et al. Hepatitis delta virus genotype IIb predominates in an endemic area, Okinawa, Japan. J Med Virol 1999;58:366-72.  Back to cited text no. 8      
9.Watanabe H, Nagayama K, Enomoto N, Chinzei R, Yamashiro T, Izumi N, et al. Chronic hepatitis delta virus infection with genotype IIb variant is correlated with progressive liver disease. J Gen Virol 2003; 84:3275-89  Back to cited text no. 9      
10.Casey JL, Niro GA, Engle RE, Vega A, Gomez H, McCarthy M, et al. Hepatitis B virus (HBV)/hepatitis D virus (HDV) coinfection in outbreaks of acute hepatitis in the Peruvian Amazon Basin: The roles of genotype III and HBV genotype F. J Infect Dis 1996;174:920-6.  Back to cited text no. 10      
11.Hoofnagle JH. Type D hepatitis. JAMA 1989;261:1321-5.  Back to cited text no. 11      
12.Sagnelli E, Stroffolini T, Ascione A, Chiaramonte M, Craxμ A, Giusti G, et al. Decrease in HDV endemicity in Italy. J Hepatol 1997;26:20-4  Back to cited text no. 12      
13.Gaeta GB, Stroffolini T, Chiaramonte M, Ascione T, Stornaiuolo G, Lobello S, et al. A vanishing disease? An Italian Multicenter Study. Hepatology 2000;32:824-7.  Back to cited text no. 13      
14.Hadziyannis SJ, Dourakis SP, Papaioannou C, Alexopoulou A, Hadziyannis ES, Gioustozi A. Changing epidemiology and spreading modalities of hepatitis delta virus infection in Greece. Prog Clin Biol Res 1993;382:259-66.  Back to cited text no. 14      
15.Huo TI, Wu JC, Lin RY, Sheng WY, Chang FY, Lee SD. Decreasing hepatitis D virus infection in Taiwan: An analysis of contributory factors. J Gastroenterol Hepatol 1997;12:747-51.  Back to cited text no. 15      
16.Erhardt A, Knuth R, Sagir A, Kirschberg O, Heintges T, Haussinger D. Socio-epidemiological data on hepatitis delta in a German university clinic-increase in patients from Eastern Europe and the former Soviet Union. Z Gastroenterol 2003;41:523-6   Back to cited text no. 16      
17.Wedemeyer H, Heidrich B, Manns MP. Hepatitis D virus infection-not a vanishing disease in Europe. Hepatology 2007;45:1331-2.  Back to cited text no. 17      
18.Gaeta GB, Stroffolini T, Smedile A, Niro G, Mele A. Hepatitis delta in Europe: Vanishing or refreshing? Hepatology 2007;46:1312-3.  Back to cited text no. 18      
19.Deπertekin H, Yalηύn K, Yakut M, Yurdaydύn C. Seropositivity for delta hepatitis in patients with chronic hepatitis B and liver cirrhosis in Turkey: A meta-analysis. Liver Int 2008;28:494-8.  Back to cited text no. 19      
20.Yurdaydύn C. Delta hepatitis in Turkey: Decreasing but not vanishing and still of concern. Turk J Gastroenterol 2006;17:74-5.  Back to cited text no. 20      
21.Guilhot S, Huang SS, Xia YP, La Monica N, Lai MM, Chisari FV. Expression of hepatitis delta virus large and small antigens in transgenic mice. J Virol 1994;68:1052-8.  Back to cited text no. 21      
22.Nisini R, Paroli M, Accapezzato D, Bonino F, Rosina F, Santantonio T, Sallusto F, et al. Human CD4+ T-cell response to hepatitis delta virus: έdentification of multiple epitopes and characterization of T-helper cytokine profiles. J Virol 1997;71:2241-51.  Back to cited text no. 22      
23.Aslan N, Yurdaydin C, Wiegand J, Greten T, Ciner A, Meyer MF, et al. Cytotoxic CD4+ T cells in viral hepatitis. J Viral Hepat 2006;13:505-14.  Back to cited text no. 23      
24.Fattovich G, Giustina G, Christensen E, Pantalena M, Zagni I, Realdi G, et al. Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. The European Concerted Action on Viral Hepatitis (Eurohep). Gut 2000;46:420-6.  Back to cited text no. 24      
25.Rosina F, Conoscitore P, Cuppone R, Rocca G, Giuliani A, Cozzolongo R, et al. Changing pattern of chronic hepatitis D in Southern Europe. Gastroenterology 1999;117:161-6.  Back to cited text no. 25      
26.Samuel D, Muller R, Alexander G, Fassati L, Ducot B, Benhamou JP, et al. Liver transplantation in European patients with the hepatitis B surface antigen. N Engl J Med 1993; 329:1842-7   Back to cited text no. 26      
27.Smedile A, Casey JL, Cote PJ, Durazzo M, Lavezzo B, Purcell RH, et al. Hepatitis D viremia following orthotopic liver transplantation involves a typical HDV virion with a hepatitis B surface antigen envelope. Hepatology 1998;27:1723-9.  Back to cited text no. 27      
28.Farci P, Mandas A, Coiana A, Lai ME, Desmet V, Van Eyken P, et al. Treatment of chronic hepatitis D with interferon alfa-2a. N Engl J Med 1994;330:88-94.  Back to cited text no. 28      
29.Madejon A, Cotonat T, Bartolome J, Castillo I, Carreno V. Treatment of chronic hepatitis D virus infection with low and high doses of interferon-alpha 2a: Utility of polymerase chain reaction in monitoring antiviral response. Hepatology 1994;19:1331-6.  Back to cited text no. 29      
30.Gaudin JL, Faure P, Godinot H, Gerard F, Trepo C. The French experience of treatment of chronic type D hepatitis with a 12-month course of interferon alpha-2B: Results of a randomized controlled trial. Liver 1995;15:45-52.  Back to cited text no. 30      
31.Farci P, Roskams T, Chessa L, Peddis G, Mazzoleni AP, Scioscia R, et al. Long-term benefit of interferon alpha therapy of chronic hepatitis D: Regression of advanced hepatic fibrosis. Gastroenterology 2004;126:1740-9.  Back to cited text no. 31      
32.Lau DT, Kleiner DE, Park Y, Di Bisceglie AM, Hoofnagle JH. Resolution of chronic delta hepatitis after 12 years of interferon alfa therapy. Gastroenterology 1999;117:1229-33.  Back to cited text no. 32      
33.Di Marco V, Giacchino R, Timitilli A, Bortolotti F, Crivellaro C, Calzia R, et al. Long-term interferon-alfa treatment of children with chronic hepatitis delta: A multicentre study. J Viral Hepat 1996;3:123-8.  Back to cited text no. 33      
34.Yurdaydin C, Bozkaya H, Karaaslan H, Onder FO, Erkan OE, Yalcin K, et al. A pilot study of two years of interferon in patients with chronic delta hepatitis. J Viral Hepat 2007;14:812-6.  Back to cited text no. 34      
35.Gunsar F, Akarca US, Ersoz G, Kobak AC, Karasu Z, Yuce G, et al. Two-year interferon therapy with or without ribavirin in chronic delta hepatitis. Antivir Ther 2005;10:721-6.  Back to cited text no. 35      
36.Niro GA, Ciancio A, Gaeta GB, Smedile A, Marrone A, Olivero A, et al. Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta. Hepatology 2006;44:713-20.  Back to cited text no. 36      
37.Erhardt A, Gerlich W, Starke C, Wend U, Donner A, Sagir A, et al. Treatment of chronic hepatitis delta with pegylated interferon-alpha2b. Liver Int 2006;26:805-10.  Back to cited text no. 37      
38.Castelnau C, Le Gal F, Ripault MP, Gordien E, Martinot-Peignoux M, Boyer N, et al. Efficacy of peginterferon alpha-2b in chronic hepatitis delta: Relevance of quantitative RT-PCR for follow-up. Hepatology 2006;44:728-35.  Back to cited text no. 38      
39.Wedemeyer H, Yurdaydin C, Dalekos G, Erhardt A, Cakaloglu Y, Degertekin H, et al. 72 week data of the HIDIT-1 trial: Multicenter randomized study comparing peginterferon a-2a plus adefovir vs. peginterferon a-2a plus placebo vs. adefovir in chronic delta hepatitis. J Hepatology 2007;46:S4   Back to cited text no. 39      
40.Yurdaydin C, Bozkaya H, Onder FO, Sentόrk H, Karaaslan H, Akdoπan M, et al . Treatment of chronic delta hepatitis with lamivudine vs. lamivudine + interferon vs. interferon. J Viral Hepat 2008:15:314-21.  Back to cited text no. 40      
41.Lau DT, Doo E, Park Y, Kleiner DE, Schmid P, Kuhns MC, et al. Lamivudine for chronic delta hepatitis. Hepatology 1999;30:546-9.  Back to cited text no. 41      
42.Niro GA, Ciancio A, Tillman HL, Lagget M, Olivero A, Perri F, et al. Lamivudine therapy in chronic delta hepatitis: A multicentre randomized-controlled pilot study. Aliment Pharmacol Ther 2005;22:227-32.  Back to cited text no. 42      
43.Yurdaydύn C, Bozkaya H, Gόrel S, Tillmann HL, Aslan N, Okηu-Heper A, et al . Famciclovir treatment of chronic delta hepatitis. J Hepatol 2002;37:266-71.  Back to cited text no. 43      
44.Peek SF, Cota PJ, Jacob JR, Toshkov IA, Hornbuckle WE, Baldwin BH, et al. Antiviral activity of clevudine [L-FMAU, (1-(2-fluoro-5-methyl-b, L-arabinofuranosyluracil)] against woodchuck hepatitis virus replication and gene expression in chronically infected woodchucks (Marmota monax). Hepatology 2001;33:254-66.  Back to cited text no. 44      
45.Casey J, Cote PJ, Toshkov IA, Chu CK, Gerin JL, Hornbuckle WE, et al. Clevudine inhibits hepatitis delta virus viremia: A pilot study of chronically infected woodchucks. Antimicrob Agents Chemother 2005;49:4396-9.  Back to cited text no. 45      
46.Glenn JS, Watson JA, Havel CM, White JM. Identification of a prenylation site in delta virus large antigen. Science 1992;256:1331-3.  Back to cited text no. 46      
47.Glenn JS, Marsters JC Jr, Greenberg HB. Use of a prenylation inhibitor as a novel antiviral agent. J Virol 1998;72:9303-6.  Back to cited text no. 47      
48.Bordier BB, Marion PL, Ohashi K, Kay MA, Greenberg HB, Casey JL, et al. A prenylation inhibitor prevents production of infectious hepatitis delta virus particles. J Virol 2002;76:10465-72.  Back to cited text no. 48      
49.Bordier BB, Ohkanda J, Liu P, Lee SY, Salazar FH, Marion PL, et al. In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus. J Clin Invest 2003;112:407-14.  Back to cited text no. 49      
50.Rowinsky EK, Windle JJ, Von Hoff DD. Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development. J Clin Oncol 1999;17:3631-52.  Back to cited text no. 50      

Top
Correspondence Address:
Cihan Yurdaydin
Department of Gastroenterology, University of Ankara Medical School, Cebeci Tip Fakultesi Hastanesi, Dikimevi, 06100 Ankara
Turkey
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-9747.58807

Rights and Permissions


    Figures

  [Figure 1], [Figure 2], [Figure 3]

This article has been cited by
1 Treatment of Chronic Delta Hepatitis: A Nine-Year Retrospective Analysis
Serda Gulsun,Recep Tekin,Fatma Bozkurt
Hepatitis Monthly. 2011; 11(9): 731
[Pubmed] | [DOI]



 

Top
 
  Search
 
  
  
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Email Alert *
    Add to My List *
* Registration required (free)  


    Abstract
    References
    Article Figures

 Article Access Statistics
    Viewed5453    
    Printed451    
    Emailed1    
    PDF Downloaded508    
    Comments [Add]    
    Cited by others 1    

Recommend this journal